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Purpose: Corneal neurotization (CN) is a novel, potentially curative surgical procedure for the treatment of neurothophic keratopathy (NK). Patients with severe NK can present with corneal opacification requiring optical keratoplasty, which would likely fail without a proper trophic support of corneal nerves in the recipient cornea. Methods: This is a pilot study on 4 patients undergoing keratoplasty after CN. Pre- and postoperative data at 12, 24 months and at the last follow-up were collected for the examination of (i) best corrected visual acuity (BCVA), (ii) slit lamp examination and photograph acquisition with and without fluorescein staining, (iii) corneal aesthesiometry, (iv) in vivo confocal microscopy of the central cornea. Neurophysiological study of the corneal reflex before corneal graft and at last follow up was performed. Results: Four female patients (47.25 ± 5.06 y.o.) underwent keratoplasty after CN (3 penetrating keratoplasty, 1 deep anterior lamellar keratoplasty). The mean interval between CN and keratoplasty was 22 (± 12) months. The mean graft survival time was 42 (± 25) months. Graft follow-up ranged from 72 to 132 months. At the final follow-up, BCVA was improved in 2 out of 4 patients. The mean corneal sensitivity was 11.9 ± 8.3 mm at last follow-up. In vivo confocal microscopy confirmed the presence of functioning nerves at the last follow-up in all patients. NK-related complications occurred in 3 eyes (2 persistent epithelial defect, 1 corneal melting). The former complication was successfully treated by autologous serum eye drops while the latter required repeated keratoplasty. Conclusions: Keratoplasty is a viable strategy to improve visual acuity in patients with corneal opacity who underwent CN for the treatment of NK. Even in the presence of functioning corneal nerves before keratoplasty, surgeons should be aware of the increased rate of NK-related complications that could require the need for repeated procedure. [ABSTRACT FROM AUTHOR]

Aim: To develop and validate a sensitive and specific bioanalytical method for the quantification of clarithromycin in human plasma using Liquid Chromatography-tandem Mass Spectrometry (LC-MS/MS). Additionally, to characterize the pharmacokinetic profile of clarithromycin, including its Absorption, Distribution, Metabolism, and Excretion (ADME) in humans. This study aims to support the clinical application and therapeutic monitoring of clarithromycin. Background: Of this study was to develop and validate a bio-analytical method for the quantification of clarithromycin in human plasma utilizing Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS). Clarithromycin, a widely used macrolide antibiotic, requires accurate and sensitive measurement in biological matrices to ensure therapeutic efficacy and monitor Pharmacokinetic (PK) profiles. The test preparation is the product being evaluated and the reference preparation is the preparation which is used to compare the test product. Pharmacokinetic or Indirect method There exist a linear relation between the drug level in the biological fluid and therapeutic response; therefore, these methods are also known as indirect methods. Solid Phase Extraction SPE is a technique to clean, separate and concentrate analyte prior to analysis. Involves passing sample through a sorbent bed that preferentially retains the analyte under the right conditions. PPT Precipitation is another method of concentration that is used extensively for biopolymer such as protein, polypeptide, etc. by increasing the concentration of a protein solution some protein can be precipitated. Materials and Methods: Human plasma samples were analyzed using a developed and validated LC-MS/MS method to quantify clarithromycin. The method underwent rigorous validation for accuracy, precision, linearity, and stability, followed by pharmacokinetic analysis to assess clarithromycin's ADME profile. Conclusion: Utilizing advanced analytical techniques such as HPLC coupled with MS, the method exhibits excellent performance characteristics, including high sensitivity, specificity, and reproducibility. he successful implementation of this method underscores its value in both clinical settings and research, contributing to better understanding and management of clarithromycin pharmacokinetics. his method's ability to provide precise and reliable data makes it an essential tool for therapeutic drug monitoring and pharmacokinetic studies of clarithromycin, ultimately contributing to improved patient care and optimized treatment outcomes. And determine the suitable parameters followed by ICH guidelines. [ABSTRACT FROM AUTHOR]

An intramuscular (IM) suspension of benzathine penicillin G (BPG) has been used as first‐line therapy for the treatment of syphilis worldwide since its approval in the 1950s. However, there are limited reports about the pharmacokinetics of BPG. A Phase 1 study was conducted on eight Japanese healthy participants to investigate the pharmacokinetics (samples collected predose to 648 h post‐dose) and safety of 2.4 million units of BPG after a single IM injection. Following administration, penicillin G, the active moiety of BPG, was absorbed slowly from the injection site with a median time to Cmax (tmax) of 48 h post‐dose. After the achievement of Cmax, concentrations of penicillin G declined slowly in a monophasic fashion with a mean apparent terminal half‐life of 189 h. Geometric mean AUCinf and Cmax were 50770 ng•h/mL and 259 ng/mL, respectively. Median time (range) above the well‐accepted therapeutic concentration (18 ng/mL) for syphilis treatment was 561 h (439‐608 h [18‐25 days]), which reached and exceeded the necessary duration of 7‐10 days for syphilis treatment. Two participants were underdosed with residual drug left in the syringe due to the high viscosity of the drug product. Only one (12.5%) participant reported a mild adverse event of nasopharyngitis, which was considered not related to the study treatment. The study results supported BPG approval in Japan as an option for syphilis treatment. [ABSTRACT FROM AUTHOR]

Duplicate analysis has been a conventional practice in the industry for ligand-binding assays (LBA), particularly for plate-based platforms like Enzyme-linked immunosorbent assay (ELISA) and Meso Scale Discovery (MSD) assays. Recent whitepapers and guidance have opened a door to exploring the implementation of single-well (singlicate) analysis approach for LBAs. Although the bioanalytical industry has actively investigated the suitability of singlicate analysis, applications in supporting regulated LBA bioanalysis are limited. The primary reason for this limitation is the absence of appropriate strategy to facilitate the transition from duplicate to singlicate analysis. In this paper we present the first case study with our data-driven approach to implement singlicate analysis in a clinical pharmacokinetics (PK) plate based LBA assay with ISR data. The central aspect of this strategy is a head-to-head comparison with Precision and Accuracy assessment in both duplicate and singlicate formats as the initial stage of assay validation. Subsequently, statistical analysis is conducted to evaluate method variability in both precision and accuracy. The results of our study indicated that there was no impactful difference between duplicate vs singlicate, affirming the suitability of singlicate analysis for the remaining steps of PK assay validation. The validation results obtained through singlicate analysis demonstrated acceptable assay performance characteristics across all validation parameters, aligning with regulatory guidance. The validated PK assay in singlicate has been employed to support a Phase I study. The appropriateness of singlicate analyses is further supported by initial Incurred Sample Reanalysis (ISR) data in which 90.1% of ISR samples fall within the acceptable criteria. [ABSTRACT FROM AUTHOR]

Thrombosis and inflammation are primary contributors to the onset and progression of ischemic stroke. The contactkinin pathway, initiated by plasma kallikrein (PK) and activated factor XII (FXIIa), functions bidirectionally with the coagulation and inflammation cascades, providing a novel target for therapeutic drug development in ischemic stroke. In this study, we identified a bat-derived oligopeptide from Myotis myotis (Borkhausen, 1797), designated LE6 (Leu-Ser-Glu-Glu-Pro-Glu, 702 Da), with considerable potential in stroke therapy due to its effects on the contact kinin pathway. Notably, LE6 demonstrated significant inhibitory effects on PK and FXIIa, with inhibition constants of 43.97 μmol/L and 6.37 μmol/L, respectively. In vitro analyses revealed that LE6 prolonged plasma recalcification time and activated partial thromboplastin time. In murine models, LE6 effectively inhibited carrageenan-induced mouse tail thrombosis, FeCl3-induced carotid artery thrombosis, and photochemically induced intracerebral thrombosis. Furthermore, LE6 significantly decreased inflammation and stroke injury in transient middle cerebral artery occlusion models. Notably, the low toxicity, hemolytic activity, and bleeding risk of LE6, along with its synthetic simplicity, underscore its clinical applicability. In conclusion, as an inhibitor of FXIIa and PK, LE6 offers potential therapeutic benefits in stroke treatment by mitigating inflammation and preventing thrombus formation. [ABSTRACT FROM AUTHOR]

An appropriately designed pharmacokinetic (PK) assay that is sensitive for antidrug antibody (ADA) impact on relevant exposure is an alternative strategy to understand the neutralizing potential of ADAs. However, guidance on how to develop such PK assays and how to confirm the functional ADA impact on exposure is missing. Here, the PK assay of a T-cell-engaging bispecific antibody, cibisatamab, was developed based on its mechanism of action (MoA). Using critical monoclonal anti-idiotypic (anti-ID) antibody positive controls as ADA surrogates, the impact on exposure was evaluated pre-clinically. In a phase I clinical trial (NCT02324257), initial data suggest that the combination of ADA and PK assays for correlation of the ADA response with cibisatamab exposure. To understand the neutralizing potential of patient-derived ADAs on drug activity, advanced ADA characterization has been performed. Structural binding analysis of ADAs to antibody domains of the drug and its impact on targeting were assessed. For this purpose, relevant patient ADA binding features were identified and compared with the specific monoclonal anti-ID antibody-positive controls. Comparable results of target binding inhibition and similar impacts on exposure suggest that the observed reduction of Cmax and Ctrough levels in patients is caused by the neutralizing potential of ADAs and allows a correlation between ADA response and loss of exposure. Therefore, the described study provides important functional aspects for the development of an appropriately designed PK assay for bispecific antibodies as an alternative option towards understanding the neutralizing ADA impact on exposure. [ABSTRACT FROM AUTHOR]

The author conducted weekly online group psychokinesis (PK) experiments between Aug. 9, 2019 and Feb. 25, 2023, with the goal of experiencing collective PK. Participant observation experiments were designed to uncover variables associated with group PK experiences rather than prove the existence of PK. Early experiments seemed to increase individual propensity for spontaneous anomalous experience. The group began attempting to influence pinwheel turning on June 12, 2020. Direct observation seemed to reduce pinwheel turning. Certain conversational elements, such as emotion and discussion of psychical research, seemed to enhance turning. A motionactivated Blink camera was incorporated into the protocol on November 8, 2021, allowing documentation of 44 pinwheel experiments. Experiences involved ostensible anomalous pinwheel turning, equipment failures, poltergeist-like events, and trickster effects. Quantitative results included: (1) Significantly more pinwheel turning, as measured by camera activations, during group meetings compared to equivalent nongroup periods; (2) Certain discussion topics were associated with rapid turning: occult traditions, psychic readings, psychical research; and (3) Other variables were associated with reduced turning: direct observation, relaxation exercise, miscellaneous discussion topics. Participants felt that the pinwheels exhibited a form of intelligence due to the pinwheel response to group discussion. Trickster effects included turning patterns that changed over time, unusual equipment failures, and 'hiding' behavior thwarting full verification. These features suggest that the replicability of findings may be limited, although a series of methodological guidelines are suggested to increase success. Grounded theory strategies allow theory development, and a new model is proposed to account for the phenomena in question. [ABSTRACT FROM AUTHOR]

The STAR GATE archive included an experiment from China of psicho-physical claim reportedly conducted on aqueous object (Wu et al, 1991). Over a time-lapse of approximately 208 seconds, total 7 phases of significant temperature deviation from the baseline temperature of 25 °C may be identified, without an explainable source of thermal generation. Not questioning the genuineness of the experiment, this work analyzes the thermal-energy transfer on the test-object that could have caused the reported temperature changes. A non-adiabatic single-compartment produces first-order low-pass responses between a thermal-input and the object's temperature. Whereas the input determines the steady-state condition, the thermal dissipation dictates the dynamics. Under the assumption of ONLY first-order responses and adjusting the input parameters including DC and AC magnitudes and time-constant of the single-compartment responses, multi-phase temperature changes resembling the reported patterns could be reconstructed. One rising phase and three falling phases with apparent oscillation were reconstructed by considering the thermal input to contain modulatory patterns of 0.4-0.5 Hz in frequency. Such modeled modulation of the thermal inputs would correspond to a correlation coefficient of 0.95 between the DC and AC magnitudes at a varying AC/ DC modulation-depth of ≤94%. The low-frequency may suggest relevance to altered neuro-electro-physiology. [ABSTRACT FROM AUTHOR]

Microbial keratitis in a post-transplant cornea should be considered a distinct entity from microbial keratitis in a non-transplant cornea. Firstly, the use of immunosuppressive treatments and sutures in corneal transplants changes the etiology of keratitis. Secondly, corneal transplant has an impact on corneal biomechanics and structure, which facilitates the spread of infection. Finally, the emergence of lamellar transplants has introduced a new form of keratitis known as interface keratitis. Given these factors, there is a clear need to update our understanding of and management strategies for microbial keratitis following corneal transplantation, especially in the era of lamellar transplants. To address this, a comprehensive review is provided, covering the incidence, risk factors, causes, and timing of microbial keratitis, as well as both clinical and surgical management approaches for its treatment in cases of penetrating and lamellar corneal transplants. [ABSTRACT FROM AUTHOR]

The use of available treatments for Fabry disease (FD) (including enzyme replacement therapy [ERT]) may be restricted by their limited symptom improvement and mode of administration. Lucerastat is currently being investigated in the MODIFY study as oral substrate reduction therapy for the treatment of FD. By reducing the net globotriaosylceramide (Gb3) load in tissues, lucerastat has disease-modifying potential to improve symptoms and delay disease progression. MODIFY is a multicenter, double-blind, randomized, placebo-controlled, parallel-group Phase 3 study (ClinicalTrial.gov: NCT03425539); here we present the rationale and design of this study. Eligible adults with a genetically confirmed diagnosis of FD and FD-specific neuropathic pain entered screening. Patients were randomized (2:1) to receive either oral lucerastat twice daily or placebo for 6 months; treatment allocation was stratified according to sex and ERT treatment status. The main objectives of MODIFY are to assess the effects of lucerastat on neuropathic pain, gastrointestinal (GI) symptoms, FD biomarkers, and determine its safety and tolerability. Neuropathic pain and GI symptoms are key features of FD that have a significant impact on quality of life. Despite various tools available to assess pain and GI symptoms, there are currently limited tools available to assess neuropathic and GI symptoms in FD, validated according to health authority guidelines. Based on FDA recommendations, we undertook a patient-reported outcome (PRO) validation study, using a novel eDiary-based PRO tool to assess the validity of evaluating neuropathic pain as a primary efficacy endpoint in MODIFY. Results from the PRO validation study are included. To date, MODIFY is the largest Phase 3 clinical study conducted in patients with FD. Enrollment to MODIFY is now complete, with 118 patients randomized. Results will be presented in a separate publication. Long-term effects of lucerastat are being assessed in the ongoing open-label extension study (NCT03737214).

BACKGROUND: Isoniazid (INH) is an important drug in many TB regimens, and unfavorable treatment outcomes can be caused by suboptimal pharmacokinetics. Dose adjustment can be personalized by measuring peak serum concentrations; however, the process involves cold-chain preservation and laboratory techniques such as liquid chromatography (LC)/mass spectrometry (MS), which are unavailable in many high-burden settings. Urine spectrophotometry could provide a low-cost alternative with simple sampling and quantification methods. METHODS: We enrolled 56 adult patients on treatment for active TB. Serum was collected at 0, 1, 2, 4, 6, and 8 h for measurement of INH concentrations using validated LC-MS/MS methods. Urine was collected at 0–4, 4–8, and 8–24 h intervals, with INH concentrations measured using colorimetric methods. RESULTS: The median peak serum concentration and total serum exposure over 24 h were 4.8 mg/L and 16.4 mg*hour/L, respectively. Area under the receiver operator characteristic curves for urine values predicting a subtherapeutic serum concentration (peak

An appropriately designed pharmacokinetic (PK) assay that is sensitive for anti-drug antibody (ADA) impact on relevant exposure is an alternative strategy to understand the neutralizing potential of ADAs. However, guidance on how to develop such PK assays and how to confirm the functional ADA impact on exposure is missing. Here, the PK assay of a T-cell-engaging bispecific antibody, cibisatamab, was developed based on its mechanism of action (MoA). Using critical monoclonal anti-idiotypic (anti-ID) antibody positive controls as ADA surrogates, the impact on exposure was evaluated pre-clinically. In a phase I clinical trial (NCT02324257), initial data suggest that the combination of ADA and PK assays for correlation of the ADA response with cibisatamab exposure. To understand the neutralizing potential of patient-derived ADAs on drug activity, advanced ADA characterization has been performed. Structural binding analysis of ADAs to antibody domains of the drug and its impact on targeting were assessed. For this purpose, relevant patient ADA binding features were identified and compared with the specific monoclonal anti-ID antibody-positive controls. Comparable results of target binding inhibition and similar impacts on exposure suggest that the observed reduction of Cmax and Ctrough levels in patients is caused by the neutralizing potential of ADAs and allows a correlation between ADA response and loss of exposure. Therefore, the described study provides important functional aspects for the development of an appropriately designed PK assay for bispecific antibodies as an alternative option towards understanding the neutralizing ADA impact on exposure.

Purpose: To assess and contrast the visual and refractive results of Descemetic deep anterior lamellar keratoplasty (DALK) and penetrating keratoplasty (PK) in the treatment of advanced keratoconus. Design: Retrospective, comparative, interventional study. Methods: This study enrolled eyes affected by keratoconus with preoperative mean keratometry ≥ 60 diopters (D) that were treated with either Descemetic DALK (30 eyes) or PK (29 eyes) by using always the same corneal diameters (8.00mm recipient; 8.25mm donor cornea) and the same suture technique (10– 0 nylon double-running 12-bites continuous suture). The outcome measures were postoperative uncorrected distance visual acuity (UDVA), best-corrected distance visual acuity (CDVA), subjective refractive astigmatism (SRAst), and keratometric astigmatism at 3mm area (SimK), spherical equivalent (SEq). Results: Postoperative visual acuity significantly improved in both groups. Mean CDVA was higher in the DALK group 3 months (DALK 0.61, PK 0.42, p< 0.05), 6 months (DALK 0.69, PK 0.44, p< 0.05), and 12 months (DALK 0.72, PK 0.45, p< 0.05) postoperatively. However, 6 months after suture removal, CDVA was not statistically different between the two groups (DALK 0.71, PK 0.75, p> 0.05). Final SRAst and SimK also were comparable between the two groups (respectively DALK 2.97, PK:2.81, p> 0.05; DALK 3.91, PK 2.37, p> 0.05). No significant statistical differences were noted for UCVA and SEq data during the entire follow-up period between the two groups. Conclusion: Both methods of corneal transplantation resulted in a notable enhancement of visual and refractive outcomes in eyes afflicted by advanced keratoconus. Descemetic DALK demonstrated superior visual acuity before suture removal, whereas DALK and PK exhibited comparable results in terms of visual acuity, refractive correction, and keratometric astigmatism after suture removal. [ABSTRACT FROM AUTHOR]

Introduction: Veterinary hemp products containing cannabidiol (CBD) and negligible psychoactive (THC) have increased popularity since hemp (with <0.3% THC) was removed from schedule 1 substances under the Controlled Substances Act in 2018. This was accompanied by increased CBD research, mostly on the short-term safety and efficacy for inflammatory and neurological conditions. It is imperative to understand how CBD is metabolized or accumulated in the body long-term, thus the goal of the present work was to determine monthly plasma CBD concentrations, as well as changes in pharmacokinetic (PK) parameters in chronically dosed dogs. Methods: The study was a masked, placebo-controlled, randomized design. Six adult beagles were assigned to placebo, 5 and 10 mg/kg/day CBD treatment groups. Dogs received oral oil treatment once daily for 36 weeks. Blood was collected once every 4 weeks pre- and postprandially for CBD plasma determination (at 0 and 2 h). Pharmacokinetics were conducted at 0, 18 and 36 weeks. Pharmacokinetics and monthly CBD plasma data of dogs who received CBD were analyzed as repeated measures over time using a mixed model, with significance at α = 0.05. Results: Average plasma CBD at 5 and 10 mg/kg were 97.3 ng/mL and 236. 8 ng/mL pre-prandial, 341 ng/mL and 1,068 ng/mL postprandial, respectively. PK parameters suggested CBD accumulation over time, with significant increases in Cmax and AUC at both the 18 and 36-week timepoints. Cmax and AUC were dose proportional. Half-life demonstrated large inter-individual variations and increased (p < 0.05) at weeks 18 and 36 compared to baseline. Volume of distribution was not affected by time or treatment, while MRT increased, and clearance decreased over time (p < 0.05). Conclusions and clinical importance: Chronic administration of CBD to healthy adult dogs led to a dose-proportional accumulation in the body for 36 weeks, which was confirmed by an increased half-life, total exposure, mean residence time and plasma peak. Our data also suggests that CBD plasma levels may have less daily variation if administered twice daily. [ABSTRACT FROM AUTHOR]

Background: The area under the curve (AUC) to minimum inhibitory concentration (MIC) ratio is proposed as a therapeutic drug-monitoring parameter for dosing vancomycin continuous infusion in methicillin-resistant Staphylococcus aureus (MRSA) infection. Individualised pharmacokinetic–pharmacodynamic (PK/PD) calculation of AUC24 may better represent therapeutic dosing than current Therapeutic Drug Monitoring (TDM) practices, targeting a Steady State Concentration of 15–25 mg/L. Aim: To compare real world TDM practice to theoretical, individualised, PK/PD target parameters utilising Bayesian predictions to steady state concentrations (Css) for outpatients on continuous vancomycin infusions. Method: A retrospective single centre study was conducted at a tertiary hospital on adult patients, enrolled in an outpatient parenteral antimicrobial therapy (OPAT) program, receiving vancomycin infusions for MRSA infection. Retrospective Bayesian dosing was modelled to target PK/PD parameters and compared to real world data. Results: Fifteen patients were evaluated with 53% (8/15) achieved target CSS during hospitalisation, and 83% (13/15) as outpatient. Median Bayesian AUC/MIC was 613 mg.h/L with CSS 25 mg/L. Patients suffering an Acute Kidney Injury (33%) had higher AUC0–24/MIC values. Retrospective Bayesian modelling demonstrated on median 250 mg/24 h lower doses than that administered was required (R2 = 0.81) which achieved AUC24/MIC median 444.8 (range 405–460) mg.h/L and CSS 18.8 (range 16.8–20.4) mg/L. Conclusion: Bayesian modelling could assist in obtaining more timely target parameters at lower doses for patients receiving continuous vancomycin infusion as part of an OPAT program, which may beget fewer adverse effects. Utilisation of personalised predictive modelling may optimise vancomycin prescribing, achieving earlier target concentrations as compared to empiric dosing regimens. [ABSTRACT FROM AUTHOR]

Abstract Background Vilobelimab, a complement 5a (C5a)-specific monoclonal antibody, reduced mortality in critically ill COVID-19 patients in a phase 3 multicentre, randomized, double-blind, placebo-controlled study. As part of the study, vilobelimab concentrations and C5a levels as well as antidrug antibodies (ADAs) to vilobelimab were analysed. Results From Oct 1, 2020 to Oct 4, 2021, 368 invasively mechanically ventilated COVID-19 patients were randomized: 177 patients were randomly assigned to receive vilobelimab while 191 patients received placebo. Pharmacokinetic sampling was only performed at sites in Western Europe. Blood samples for vilobelimab measurements were available for 93 of 177 (53%) patients in the vilobelimab group and 99 of 191 (52%) patients in the placebo group. On day 8, after three infusions, mean vilobelimab (trough) concentrations ranged from 21,799.3 to 302,972.1 ng/mL (geometric mean 137,881.3 ng/mL). Blood samples for C5a measurements were available for 94 of 177 (53%) patients in the vilobelimab group and 99 of 191 (52%) patients in the placebo group. At screening, C5a levels were highly elevated and comparable between groups. In the vilobelimab group, median C5a levels were 118.3 ng/mL [IQR 71.2–168.2 ng/mL] and in the placebo group, median C5a levels were 104.6 ng/mL [IQR 77.5–156.6 ng/mL]. By day 8, median C5a levels were reduced by 87% in the vilobelimab group (median 14.5 ng/mL [IQR 9.5–21.0 ng/mL], p

LNA-i-miR-221 is a novel microRNA(miRNA)-221 inhibitor designed for the treatment of human malignancies. It has recently undergone phase 1 clinical trial (P1CT) and early pharmacokinetics (PKs) data in cancer patients are now available. We previously used multiple allometric interspecies scaling methods to draw inferences about LNA-i-miR-221 PKs in humans and estimated the patient dose based on the safe and pharmacodynamic (PD) active dose observed in mice, therefore providing a framework for the definition of safe starting and escalation doses for the P1CT. The preliminary data collected during the P1CT showed that the LNA-i-miR-221 anticipated doses, according to our human PK estimation approach, were indeed well tolerated and effective. PD data demonstrated concentration-dependent downregulation of miR-221 and upregulation of its CDKN1B/p27 and PTEN canonical targets as well as stable disease in 8 (50.0%) patients and partial response in 1 (6.3%) colorectal cancer case. Here, we detail the experimentally evaluated PK parameters of LNA-i-miR-221 in human, using both a non-compartmental and a population PKs approach. The population approach was adequately described by a three-compartments model with first-order elimination. The recorded age, sex and body weight of patients were evaluated as potential covariates. The estimated typical population parameter values were clearance (CL = 200 mL/h/kg), central volume of distribution (V1 = 45 mL/kg), peripheral volume of distribution (V2 = 200 mL/kg, volume of the second peripheral compartment V3 = 930 mL/h/kg) and inter-compartmental clearance (Q2 = 480 mL/h/kg and Q3 = 68 mL/h/kg). Age was found to be a predictor of Q3, with a statistically significant correlation. This work aimed also at retrospectively comparing the measured plasmatic clearance values with those predicted by different allometric scaling approaches. Our comparative analysis showed that the most accurate prediction was achieved by applying the single species allometric scaling approach and that the use of more than one species in allometric scaling to predict therapeutic oligonucleotides PKs would not necessarily generate the best prediction. Finally, our predictive approach was found accurate not only in predicting the main PK parameters in human but suggesting the range of effective and safe dose to be applied in the next clinic phase 2.

ABSTRACTAspartic acid (Asp) isomerization is a spontaneous non-enzymatic post-translation modification causing a change in the structure of the protein backbone, which is commonly observed in therapeutic antibodies during manufacturing and storage. The Asps in Asp–Gly (DG), Asp–Ser (DS), and Asp–Thr (DT) motifs in the structurally flexible regions, such as complementarity-determining regions (CDRs) in antibodies, are often found to have high rate of isomerization, and they are considered “hot spots” in antibodies. In contrast, the Asp-His (DH) motif is usually considered a silent spot with low isomerization propensity. However, in monoclonal antibody mAb-a, the isomerization rate of an Asp residue, Asp55, in the aspartic acid-histidine-lysine (DHK) motif present in CDRH2 was found to be unexpectedly high. By determining the conformation of DHK motif in the crystal structure of mAb-a, we found that the Cgamma of the Asp side chain carbonyl group and the back bone amide nitrogen of successor His were in proximal contact, which facilitates the formation of succinimide intermediate, and the +2 Lys played an important role in stabilizing such conformation. The contributing roles of the His and Lys residues in DHK motif were also verified using a series of synthetic peptides. This study identified a novel Asp isomerization hot spot, DHK, and the structural-based molecular mechanism was revealed. When 20% Asp55 isomerization in this DHK motif occurred in mAb-a, antigen binding activity reduced to 54%, but the pharmacokinetics in rat was not affected significantly. Although Asp isomerization of DHK motif in CDR does not appear to have a negative impact on PK, DHK motifs in the CDRs of antibody therapeutics should be removed, considering the high propensity of isomerization and impact on antibody activity and stability.

Certain classes of antibiotics show "concentration dependent" antimicrobial activity; higher concentrations result in increased bacterial killing rates, in contrast to "time dependent antibiotics", which show antimicrobial activity that depends on the time that antibiotic concentrations remain above the MIC. Aminoglycosides and fluoroquinolones are still widely used concentration-dependent antibiotics. These antibiotics are not hydrolyzed by beta-lactamases and are less sensitive to the inoculum effect, which can be defined as an increased MIC for the antibiotic in the presence of a relatively higher bacterial load (inoculum). In addition, they possess a relatively long Post-Antibiotic Effect (PAE), which can be defined as the absence of bacterial growth when antibiotic concentrations fall below the MIC. These characteristics make them interesting complementary antibiotics in the management of Multi-Drug Resistant (MDR) bacteria and/or (neutropenic) patients with severe sepsis. Global surveillance studies have shown that up to 90% of MDR Gram-negative bacteria still remain susceptible to aminoglycosides, depending on the susceptibility breakpoint (e.g., CLSI or EUCAST) being applied. This percentage is notably lower for fluoroquinolones but depends on the region, type of organism, and mechanism of resistance involved. Daily (high-dose) dosing of aminoglycosides for less than one week has been associated with significantly less nephro/oto toxicity and improved target attainment. Furthermore, higher-than-conventional dosing of fluoroquinolones has been linked to improved clinical outcomes. Beta-lactam antibiotics are the recommended backbone of therapy for severe sepsis. Since these antibiotics are time-dependent, the addition of a second concentration-dependent antibiotic could serve to quickly lower the bacterial inoculum, create PAE, and reduce Penicillin-Binding Protein (PBP) expression. Inadequate antibiotic levels at the site of infection, especially in the presence of high inoculum infections, have been shown to be important risk factors for inadequate resistance suppression and therapeutic failure. Therefore, in the early phase of severe sepsis, effort should be made to optimize the dose and quickly lower the inoculum. In this article, the authors propose a novel concept of "Inoculum Based Dosing" in which the decision for antibiotic dosing regimens and/or combination therapy is not only based on the PK parameters of the patient, but also on the presumed inoculum size. Once the inoculum has been lowered, indirectly reflected by clinical improvement, treatment simplification should be considered to further treat the infection. [ABSTRACT FROM AUTHOR]

In this explanatory sequential mixed method study, the researcher attempted to investigate the EFL teachers’ status of CK, PK, PCK, classroom practice and the relationships among these variables. Comprehensive and purposive sampling techniques were used. Quantitative and qualitative data analyses methods were employed in the study. The least knowledge the teachers owned was CK whereas classroom practice was found to be relatively the highest. They had moderate PK in assessing students’ understanding of topics, in drawing up clear classroom rules, creating a friendly atmosphere, and developing a good relationship with students. However, the overall finding revealed that the teachers were not well equipped with PK. They had moderate PCK in designing instructional objectives and context, and in using appropriate examples to explain concepts related to the subject matter whereas their knowledge of students’ understandings and misunderstandings was inadequate. They had low knowledge to diagnose the notions that were problematic for students and to think why these concepts became difficult. There was a strong positive correlation between CK and classroom practice. The correlation between CK and PK was fair whereas there was a weak positive correlation between PK and classroom practice. There was not statistically significant relationship between PCK and classroom practice. [ABSTRACT FROM AUTHOR]

This paper proposes a framework that supports both free will and anomalous mind-matter interaction (psychokinesis). I begin by considering the argument by the physicist Sean Carroll that the laws of physics as we understand them rule out psychokinesis (and other modes of psi), and find his claims problematic, in part due to misunderstandings of arguments borrowed from David Hume. I proceed to consider a more dispositional notion of causality (in contrast to one characterized by universal and necessary laws) which is more hospitable to both psychokinesis and free will. I then incorporate recent work from the philosophy of mind and science to arrive at a framework that supports real volition and psychokinesis, which are intimately linked. This approach is fundamentally dispositional but grounded in an ontologically prior field of awareness and potentiality. I also consider that the regularities (or causal natures) we observe in our physical world are ultimately supported by teleological “intentions” within a nonlocal, mind-like quantum ground.

Lumefantrine (LMN) is one of the first-line drugs in the treatment of malaria due to its long circulation half-life, which results in enhanced effectiveness against drug-resistant strains of malaria. However, LMN's therapeutic efficacy is diminished due to its low bioavailability when dosed as a crystalline solid. The goal of this work was to produce low-cost, highly bioavailable, stable LMN powders for oral delivery that would be suitable for global health applications. We report the development of a LMN nanoparticle formulation and the translation of that formulation from laboratory to industrial scale. We applied Flash NanoPrecipitation (FNP) to develop nanoparticles with 90% LMN loading and sizes of 200-260 nm. The integrated process involves nanoparticle formation, concentration by tangential flow ultrafiltration, and then spray drying to obtain a dry powder. The final powders are readily redispersible and stable over accelerated aging conditions (50°C, 75% RH, open vial) for at least 4 weeks and give equivalent and fast drug release kinetics in both simulated fed and fasted state intestinal fluids, making them suitable for pediatric administration. The nanoparticle-based formulations increase the bioavailability of LMN 4.8-fold in vivo when compared to the control crystalline LMN. We describe the translation of the laboratory-scale process at Princeton University to the clinical manufacturing scale at WuXi AppTec. [Display omitted] [ABSTRACT FROM AUTHOR]

Subcutaneously administered drugs are growing in popularity for both large and small molecule drugs. However, development of these systems – particularly generics – is slowed due to a lack of formal guidance regarding preclinical testing and in vitro – in vivo correlations (IVIVC). Many of these methods, while appropriate for oral drugs, may not be optimized for the complex injection site physiologies, and release rate and absorption mechanisms of subcutaneous drugs. Current limitations for formulation design and IVIVC can be supported by implementing mechanistic, computational methods. These methods can help to inform drug development by identifying key drug and formulation attributes, and their effects on drug release rates. This perspective, therefore, addresses current guidelines in place for oral IVIVC development, how they may differ for subcutaneously administered compounds, and how modeling and simulation can be implemented to inform design of these products. As such, integration of modeling and simulation with current IVIVC systems can help in driving the development of subcutaneous injectables. [ABSTRACT FROM AUTHOR]

The increasing complexity and diversity of antibody–drug conjugates (ADCs) have led to a need for comprehensive and informative bioanalytical methods to enhance pharmacokinetic (PK) understanding. This study aimed to evaluate the feasibility of a hybrid immunoaffinity (IA) capture microflow LC–MS/MS (μLC-MS/MS) method for ADC analysis, utilizing a minimal sample volume for PK assessments in a preclinical study. A robust workflow was established for the quantitative analysis of ADCs by the implementation of solid-phase extraction (SPE) and semi-automation in µLC-MS/MS. Utilizing the µLC-MS/MS approach in conjunction with 1 µL of ADC-dosed mouse plasma sample volume, standard curves of two representative surrogate peptides for total antibody (heavy chain, HC) and intact antibody (light chain, LC) ranged from 1.00 ng/mL (LLOQ) to 5000 ng/mL with correlation coefficients (r2) values of > 0.99. The linear range of the standard curve for payload as a surrogate for the concentration of total ADC was from 0.5 ng/mL (LLOQ) to 2000 ng/mL with high accuracy and precision (< 10% CV at all concentrations). Moreover, a high correlation of concentrations of total antibody between two assay approaches (µLC-MS and ELISA) was achieved with less than 20% difference at all time points, indicating that the two methods are comparable in quantitation of total antibody in plasma samples. The µLC-MS platform demonstrated a greater dynamic range, sensitivity, robustness, and good reproducibility. These findings demonstrated that the cost-effective µLC-MS method can reduce reagent consumption and minimize the use of mice plasma samples while providing more comprehensive information about ADCs being analyzed, including the total antibody, intact antibody, and total ADC. [ABSTRACT FROM AUTHOR]

Background: Vilobelimab, a complement 5a (C5a)-specific monoclonal antibody, reduced mortality in critically ill COVID-19 patients in a phase 3 multicentre, randomized, double-blind, placebo-controlled study. As part of the study, vilobelimab concentrations and C5a levels as well as antidrug antibodies (ADAs) to vilobelimab were analysed. Results: From Oct 1, 2020 to Oct 4, 2021, 368 invasively mechanically ventilated COVID-19 patients were randomized: 177 patients were randomly assigned to receive vilobelimab while 191 patients received placebo. Pharmacokinetic sampling was only performed at sites in Western Europe. Blood samples for vilobelimab measurements were available for 93 of 177 (53%) patients in the vilobelimab group and 99 of 191 (52%) patients in the placebo group. On day 8, after three infusions, mean vilobelimab (trough) concentrations ranged from 21,799.3 to 302,972.1 ng/mL (geometric mean 137,881.3 ng/mL). Blood samples for C5a measurements were available for 94 of 177 (53%) patients in the vilobelimab group and 99 of 191 (52%) patients in the placebo group. At screening, C5a levels were highly elevated and comparable between groups. In the vilobelimab group, median C5a levels were 118.3 ng/mL [IQR 71.2–168.2 ng/mL] and in the placebo group, median C5a levels were 104.6 ng/mL [IQR 77.5–156.6 ng/mL]. By day 8, median C5a levels were reduced by 87% in the vilobelimab group (median 14.5 ng/mL [IQR 9.5–21.0 ng/mL], p < 0.001) versus an 11% increase in the placebo group (median 119.2 ng/mL [IQR 85.9–152.1 ng/mL]). Beyond day 8, though plasma sampling was sparse, C5a levels did not reach screening levels in the vilobelimab group while C5a levels remained elevated in the placebo group. Treatment-emergent ADAs were observed in one patient in the vilobelimab group at hospital discharge on day 40 and in one patient in the placebo group at hospital discharge on day 25. Conclusions: This analysis shows that vilobelimab efficiently inhibits C5a in critically ill COVID-19 patients. There was no evidence of immunogenicity associated with vilobelimab treatment. Trialregistration ClinicalTrials.gov, NCT04333420. Registered 3 April 2020, https://clinicaltrials.gov/ct2/show/NCT04333420 [ABSTRACT FROM AUTHOR]

Parapsychology is on the forefront of scientific research, but certainly draws much debate around the academic world. But we cannot accept the blind denial of so-called skeptics. In China, parapsychology is the study of mainly special people and their special functions. In this article, we present findings from recent Chinese research in parapsychology. We report on the psi potential of blind children and the alleged paranormal abilities of Yang De-Gui, Chen Qui-Shi, and others. We also discuss some key findings presented at three parapsychology conferences at Kunming, China, that suggest psi experimentation can be carried out using scientific instruments. Though the functions of these special people vary with age, most appear stable and repeatable. Chinese parapsychology can be viewed in context with China’s rich traditional culture. [ABSTRACT FROM AUTHOR]

IntroductionVeterinary hemp products containing cannabidiol (CBD) and negligible psychoactive (THC) have increased popularity since hemp (with

Dehua Zhao, Xiaoqing Long, Jisheng Wang Department of Clinical Pharmacy, The Third Hospital of Mianyang (Sichuan Mental Health Center), Mianyang, Sichuan, People’s Republic of ChinaCorrespondence: Dehua Zhao; Jisheng Wang, Email zhaoyaoshi0566@163.com; wangjishengyaoshi@163.comAbstract: Poly (ADP-ribose) polymerase (PARP) inhibitors are small-molecule inhibitors of PARP enzymes (including PARP1, PARP2, and PARP3) that exhibit activity against tumor cells with defects in DNA repair. In recent years, five PARP inhibitors, olaparib, niraparib, rucaparib, talazoparib and veliparib, have been developed for the treatment of solid tumors, particularly in patients with breast-related cancer antigen (BRCA) 1/2 mutations, or those without a functional homologous recombination repair pathway. These novel treatments exhibit improved efficacy and toxicity when compared to conventional chemotherapy agents. The five PARP inhibitors are eliminated primarily via the liver and kidneys, hepatic or renal impairment may significantly affect their pharmacokinetics (PK). Therefore, it is important to know the effects of hepatic or renal impairment on the PK and safety of PARP inhibitors. In this review, we characterize and summarize the effects of hepatic and renal function on the PK of PARP inhibitors and provide specific recommendations for clinicians when prescribing PARP inhibitors in patients with hepatic or renal impairment.Keywords: PARP inhibitors, cancer, hepatic impairment, renal impairment, PK

Cardiovascular diseases (CVDs) are the world's leading cause of death, accounting for 32% of all fatalities. Although therapeutic agents are available for CVDs, however, most of them have significant limitations such as the time-dependency effect, hypotension, and bradycardia. To overcome the limitations of current pharmacological therapies, new molecular targets and pathways need to be identified and investigated to provide better treatment options for CVDs. Recent evidence suggested the involvement of pyruvate kinase M2 (PKM2) and targeting PKM2 by its modulators (inhibitors and activators) has shown promising results in several CVDs. PKM2 regulates gene activation in the context of apoptosis, mitosis, hypoxia, inflammation, and metabolic reprogramming. PKM2 modulators might have a significant impact on the molecular pathways involved in CVD pathogenesis. Therefore, PKM2 modulators can be one of the therapeutic options for CVDs. This review provides an insight into PKM2 involvement in various CVDs along with their therapeutic potential. [ABSTRACT FROM AUTHOR]

Background: Assessment of the safety of heartworm preventatives in dogs with pre-existing patent heartworm (Dirofilaria immitis) infections is necessary because rapid adult worm and microfilarial death can lead to severe clinical complications, including thromboembolism and anaphylactic shock in dogs. The aim of this study was to determine the clinical safety of Simparica Trio® (sarolaner, pyrantel, moxidectin) in heartworm-infected dogs and the degree of microfilaricidal and adulticidal activity of three consecutive monthly treatments of Simparica Trio. Methods: Twenty-four laboratory Beagle dogs were implanted with 10 male and 10 female D. immitis (ZoeKY isolate), and once infection was patent, they were randomized equally among three groups to receive no treatment, 1× or 3× the maximum recommended label dose of Simparica Trio. Dogs in the treated groups received Simparica Trio on days 0, 28 and 56. In-life assessments included body weight, physical examinations, clinical observations, daily general health observations, a quantitative estimate of food consumption and blood collections for pharmacokinetic (PK) analysis, microfilariae (MF) counts and D. immitis antigen testing. At the end of the study the heart, lungs and pleural and peritoneal cavities were examined for adult D. immitis worms. Results: Simparica Trio was generally well tolerated. Emesis occurred at low frequency in all groups including control. Abnormal stool occurred occasionally in the 1× and 3× groups throughout the 3-month study. Fever (> 104 °F/40 °C) was recorded in one 1× and one 3× dog 1 day after the first dose and resolved by the following day. No severe hypersensitivity reactions occurred. The mean number of circulating microfilariae (MF) counts in the control group increased from 12,000/ml at study start (Day 0) to > 20,000/ml at Day 28 and remained > 20,000/ml for the duration of the study. The least squares means of circulating MF were reduced by 69.8% on Day 1 and 97.4% on Day 7 for the 1× group and remained at > 99% lower than the control group for the remainder of the study. Similarly, least squares means of circulating MF were reduced by 85.3% on Day 1 and 93.9% on Day 7 for the 3× group and remained > 98% lower than the control group for the remainder of the study. At the end of the study, the mean number of implanted adult worms recovered was < 10 per sex in all groups with 90%, 85% and 75% of live adult heartworms recovered in control, 1× and 3× treatment groups, respectively. Low numbers of dead adult worms were recovered in 1× and 3×, with none in control. Following each dose, the moxidectin and sarolaner AUC and Cmax had close to dose proportional increases. Conclusions: This study demonstrated that Simparica Trio (sarolaner, pyrantel, moxidectin) was well tolerated when administered to heartworm-positive dogs at 1× and 3× the maximum recommended dose at 28-day intervals for 3 consecutive months. Simparica Trio significantly reduced microfilaria counts in both treatment groups, without significant clinical consequences. At the doses administered, Simparica Trio had minor adulticidal activity but resulted in no clinical sequelae. [ABSTRACT FROM AUTHOR]

Pharmacokinetic (PK) analysis is an integral part of drug development. Health agency guidance provides development and validation recommendations for PK bioanalytical methods run in one laboratory. However, as a drug development program progresses, a PK bioanalytical method may need to be run in more than one laboratory. Additionally, a PK bioanalytical method format may change and a new method platform may be validated and implemented during the drug development cycle. Here we describe the cross validation strategy for comparisons of two validated bioanalytical methods used to generate PK data within the same study or across different studies. Current guidance for cross validations is limited and, therefore, Genentech, Inc. has developed a cross validation experimental strategy that utilizes incurred samples along with a comprehensive statistical analysis. One hundred incurred study samples over the applicable range of concentrations are selected based on four quartiles (Q) of in-study concentration levels. The samples are assayed once in the two bioanalytical methods. Bioanalytical method equivalency is assessed for the 100 samples based on pre-specified acceptability criterion: the two methods are considered equivalent if the percent differences in the lower and upper bound limits of the 90 % confidence interval (CI) are both within ±30 %. Quartile by concentration analysis using the same criterion may also need to be performed. A Bland-Altman plot of the percent difference of sample concentrations versus the mean concentration of each sample is also created to help further characterize the data. This strategy is a robust assessment of PK bioanalytical method equivalency and includes subgroup analyses by concentration to assess for biases. This strategy was implemented in two case studies: 1) two different laboratories using the same bioanalytical method and 2) a bioanalytical method platform change from enzyme-linked immunosorbent assay (ELISA) to multiplexing immunoaffinity (IA) liquid chromatography tandem mass spectrometry (IA LC-MS/MS). • Cross validation is an assessment of two or more bioanalytical methods to show their equivalency. • The cross validation strategy developed at Genentech, Inc. utilizes incurred matrix samples. • Two methods are equivalent if the 90 % CI limits of the mean percent difference of concentrations are within ±30 %. • Case Study 1 describes the cross validation of a pharmacokinetic (PK) bioanalytical method between two different labs. • Case Study 2 describes the cross validation of two different PK bioanalytical method platforms. [ABSTRACT FROM AUTHOR]

In plants, as in all eukaryotes, the cell cycle is regulated by the heterodimer formed by cyclins (Cycs) and cyclin-dependent kinases (CDKs), that phosphorylate serine/threonine residues in target proteins. The extensive involvement of these heterodimers in nuclear cell cycle-related processes has been demonstrated. However, recent findings have linked Cyc-CDK complexes to the regulation of cytosolic processes, including various metabolic pathways, suggesting close coordination between the cell cycle and catabolic/anabolic processes to maintain cellular energy homeostasis. This study extends the analysis of Cyc-CDK complex regulation in maize to two key regulators of glycolysis: phosphofructose kinase (PFK) and pyruvate kinase (PK). Both are cytosolic enzymes, highly regulated positively and negatively by different metabolites, showing a similar activation pattern in their homotetrameric form and low activity when as dimers/monomers. Each enzyme exhibits two putative minimal phosphorylation motives for Cyc-CDKs, conserved in some plant species and in four (PFK) and three (PK) isoforms in maize. This work demonstrates that both enzymes are active with fluctuating levels of activity along maize germination; also, that they associate with different maize Cycs and CDKs as demonstrated by pull-down assays, as well as their in vitro phosphorylation by recombinant CycD;2-CDKA or CycD2;2-CDKB complexes. Additionally, the inhibition of PFK and PK activity following phosphorylation by active Cycs-CDKB complexes obtained by immunoprecipitation from imbibed embryonic axis protein extracts suggests a narrow and negative regulation of glycolysis as the cell cycle progresses. A decreased carbon flow through this pathway is proposed to divert carbon from sugars towards the oxidative pentose phosphate pathway, thereby promoting de novo nucleic acid synthesis precursors to stimulate cell cycle progression. [Display omitted] Maize PFK and PK isoforms contain two CDK phosphorylation motifs. PFK and PK interacted distinctively with members of the Cyclin/CDK complexes in maize PFK and PK were phosphorylated in vitro by recombinant CycD2;2/CDK (A/B) The activities of PFK and PK were inhibited following phosphorylation by Cyc/CDKB [ABSTRACT FROM AUTHOR]

A series of amino-2-cyclohexyl ester derivatives were studied for their ion channel blocking and antiarrhythmic actions in the rat and a structure-activity analysis was conducted. The compounds are similar in chemical structure except for ionizable amine groups (pK values 6.1-8.9) and the positional arrangements of aromatic naphthyl moieties. Ventricular arrhythmias were produced in rats by coronary-artery occlusion or electrical stimulation. The electrophysiological effects of these compounds on rat heart sodium channels (Nav1.5) expressed in Xenopus laevis oocytes and transient outward potassium currents (Kv4.3) from isolated rat ventricular myocytes were examined. The compounds reduced the incidence of ischemia-related arrhythmias and increased current threshold for induction of ventricular fibrillo-flutter (VFt) dose-dependently. As pK increased compounds showed a diminished effectiveness against ischemia-induced arrhythmias, and were less selective for ischemia- versus electrically-induced arrhythmias. Where tested, compounds produced a concentration-dependent tonic block of Nav1.5 channels. An increased potency for inhibition of Nav1.5 occurred when the external pH (pHo) was reduced to 6.5. Some compounds inhibited Kv4.3 in a pH-independent manner. Overall, the differences in antiarrhythmic and ion channel blocking properties in this series of compounds can be explained by differences in chemical structure. Antiarrhythmic activity for the amino-2-cyclohexyl ester derivatives is likely a function of mixed ion channel blockade in ischemic myocardium. These studies show that drug inhibition of Nav1.5 occurred at lower concentrations than Kv4.3 and was more sensitive to changes in the ionizable amine groups rather than on positional arrangements of the naphthyl constituents. These results offer insight into antiarrhythmic mechanisms of drug-ion channel interactions.

Background: Capecitabine is one of the fluoropyrimidine anticancer agents which is extensively used in the management of colorectal cancer. We have noticed a discrepancy between the doses we are using in our patients and the recommended dosing regimen. Thus, this study aims to assess the pharmacokinetic parameters of capecitabine and its metabolites in colorectal cancer patients and report some clinical outcomes. Methods: This study is a prospective observational pharmacokinetic study. It was conducted at the Oncology Center at King Saud University Medical City. The study included adult patients who received capecitabine for any stage of colorectal cancer. Blood samples were collected following the oral administration of capecitabine. Capecitabine and its metabolites concentration in plasma were determined using HPLC and pharmacokinetic parameters were estimated using PKanalix software. Results: The study included 30 colorectal cancer patients with a mean age of 58 ± 9.5 years and ECOG Performance Status of 0–1. 60 % of the patients were in stage IV. The average total daily dose was 1265 ± 350 mg/m2/day. Cmax for capecitabine was 5.2 ± 1.3 μg/ mL and Tmax was 1 ± 0.25 h. AUClast for capecitabine was 28 ± 10 μg.h/ mL. Vdobs and Clobs for capecitabine were 186 ± 28 L and 775 ± 213 mL/min, respectively. Calculated half-life (t1/2) was 2.7 h. Half of our patients showed partial tumor response and 20% showed stable disease. Only two patients had to discontinue the treatment because of the toxicity. Conclusion: Despite using lower doses, capecitabine and its metabolites parameters were found to be similar to previous studies except for the longer half-life found in our patients. In addition, lower doses of capecitabine showed acceptable response rate which might indicate that higher doses are not always necessary to achieve desired therapeutic effect.

This study is concerned with the development of an optimum method for identification of supercritical CO2 permeability in thermoplastic films with moderate to excellent barrier properties namely, High-Density Polyethylene (HDPE), Raised-Temperature Polyethylene (PE-RT), Polyvinylidene Fluoride (PVDF) and aliphatic Polyketone (PK) at elevated temperatures (40 °C−82 °C). A high-temperature/high-pressure permeation cell was designed based on the “closed-volume/variable pressure” standard test method. The identified gas transport properties using the time lag method yielded significant error particularly for PVDF and PK, which was ascribed to the sole reliance on the accumulated pressure-rate in steady-state. This error was minimized using the Non-Linear Regression (NLR) by utilizing the full range of measured data including the transient state. The coefficient of determination between the measured and modeled data using NLR was quantified above 0.99 for all the polymers at the entire examined temperature range. The 1.4 % higher degree of crystallinity and 28.5 % smaller spherulite size caused 13.3 % higher diffusivity and 8.6 % lower solubility in PE-RT when compared with HDPE at 82°C. As a result of this trade-off, PE-RT exhibited only 3.5 % higher permeability than HDPE. The developed generalized temperature-dependent model provided the essential data for design optimization of gas barrier performance in multilayer high-temperature pressure-vessels.

A vast evolution of drug modalities has occurred over the last several decades. Novel modalities such as cell and gene therapies have proven to be efficacious for numerous clinical indications–primarily in rare disease and immune oncology. Because of this success, drug developers are heavily investing in these novel modalities. Given the complexity of these therapeutics, a variety of bioanalytical techniques are employed to fully characterize the pharmacokinetics of these therapies in clinical studies. Industry trends indicate that quantitative PCR (qPCR) and multiparameter flow cytometry are both valuable in determining the pharmacokinetics, i.e. cellular kinetics, of cell therapies. This manuscript will evaluate the pros and cons of both techniques and highlight regulatory guidance on assays for measuring cellular kinetics. Moreover, common considerations when developing these assays will be addressed. [ABSTRACT FROM AUTHOR]

The article has discussed a step-by-step algorithm for developing population pharmacokinetics models in the Lixoft Monolix software. Features of population pharmacokinetics study’s methodology have described. Special attention is paid to the advantages of the compartmental approach and nonlinear mixed effects modeling in study of pharmacokinetics. Methods for estimating population pharmacokinetic parameters and its implementation in software are described.